The present invention relates to the (R)- and (S)-enantiomers of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile, pharmaceutical compositions containing same, and a method for promoting hair growth employing such enantiomers.
Potassium channel openers such as minoxidil (Upjohn), pinacidil (Lilly) and diazoxide (Shiseido and Schering-Plough) are known for their hair growth stimulating activity. Thus, U.S. Pat. Nos. 4,596,812 and 4,139,619 disclose use of minoxidil in the treatment of male pattern baldness, alopecia areata and balding in females. U.S. Pat. No. 4,057,636 discloses pinacidil. U.S. Pat. No. DE 3,827,467A discloses combinations of minoxidil and hydrocortisone or retinoids.
U.S. Pat. No. 5,011,837 to Atwal et al discloses aryl cyanoguanidines which possess potassium channel activating activity and are useful therapy for hypertension and other cardiovascular disorders, for various central nervous system disorders, kidney and urinary problems as well as for the promotion of hair growth, for example in the treatment of male pattern baldness (alopecia). These aryl cyanoguanidines have the structure 
and its possible tautomers 
including pharmaceutically acceptable salts, wherein
R1 is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, arylalkyl or cycloalkylalkyl;
R2 is 
R3 and R4 are each independently selected form xe2x80x94R2, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halo, alkoxy, xe2x80x94NHalkyl, xe2x80x94N-(alkyl)2, xe2x80x94S-alkyl, xe2x80x94O-aryl-alkyl, xe2x80x94Sxe2x80x94arylalkyl or xe2x80x94S-aryl, xe2x80x94O-aryl, xe2x80x94NHaryl-alkyl, or R2 and R3 taken together are a group which form a ring with the two carbon atoms to which they are attached, which group is selected from 
wherein
m=1 or 2,
n=3-5,
p=2-4,
X is 0, NR5, CH2; and
R5 is hydrogen or R1.
Example 1 of U.S. Pat. No. 5,011,837 discloses the preparation of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl) amino]benzonitrile 
in the form of its racemic mixture.
PCT Application WO 92/02225 discloses a combination of a potassium channel opener and a 5-xcex1-reductase inhibitor for promoting hair growth.
PCT Application WO 92/09259A discloses use of an androgen blocker and a potassium channel activator for stimulation of hair growth.
In accordance with the present invention, it has been unexpectedly found that the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile, including pharmaceutically acceptable salts, thereof exhibits remarkable hair growth promoting activity which is superior in such regard to the corresponding (S)-enantiomer and the racemic mixture of such enantiomers. In fact, it has been found that the (R)-enantiomer is surprisingly and unexpectedly more effective in stimulating hair follicles to produce hair growth at a substantially faster rate as compared to the corresponding (S)-enantiomer.
The above (R)-enantiomer of the invention has the structure I 
The (R)-enantiomer I will be in substantially pure form, that is, will be at least 99% pure (R)-enantiomer and will at most contain 1% (S)-enantiomer.
In addition, in accordance with the present invention, it has been found that the (S)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile, including pharmaceutically acceptable salts thereof, exhibits excellent hair growth promoting activity.
The above (S)-enantiomer of the invention has the structure II 
The (S)-enantiomer II will be in substantially pure form, that is, will be at least 99% pure (S)-enantiomer and will at most contain 1% (R)-enantiomer.
The enantiomers of the invention form salts with a variety of inorganic and organic acids. The non-toxic pharmaceutically acceptable salts are preferred, although other salts may also be useful in isolating or purifying the product. Such pharmaceutically acceptable salts include those formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid, and the like. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates.
The present invention also includes pharmaceutical compositions containing the (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
In addition, the present invention also includes pharmaceutical compositions containing the (S)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
The (R)-enantiomer of the invention, that is, (R)-4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile may be prepared according to the following reaction sequence: 
The (S)-enantiomer of the invention, that is (S)-4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile may be prepared according to the above reaction sequence for preparation of the (R)-enantiomer except that (S)-xcex1-methylbenzylamine is employed in place of (R)-xcex1-methylbenzylamine to eventually form 
which is reacted with the 4-cyano-Nxe2x80x2-(4-cyanophenyl)thiourea, monosodium salt to form the (S)-enantiomer (II).
The (R)-enantiomer I of the invention or the (S)-enantiomer II of the invention may be formulation with other hair growth promoting compounds such as the potassium channel openers minoxidil (Upjohn) and/or diazoxide (Shiseido and Schering-Plough), as well as cromakalim and pinacidil; a 5-xcex1-reductase inhibitor such as finasteride (Merck""s Proscar(copyright)), terazosin HCl (Abbott""s Hytrin(copyright)), or doxaosin mesylate (Pfizer""s Cardura(copyright)); and/or an androgen blocker such as 4-(5-methoxyheptyl)-hexahydro-2(1H)-pentalenone as disclosed in PCT Application WO 92/09259A, vasoconstrictors such as betamethasone dipropionate, corticosteroids such as hydrocortisone, and scopolamine, and cyproterone acetate.
The enantiomers of the invention may be administered via topical, oral, parenteral or rectal routes as described in U.S. Pat. No. 5,011,837 (incorporated herein by reference), with topical being preferred. Thus, the enantiomers of the invention in suitable topical formulations are applied to the skin region where hair growth is desired.
Typical topical formulations for use herein will include conventional ointments, creams, lotions, waxes, gels, pastes, jellies, sprays, aerosols and the like in aqueous or non-aqueous formulations. Examples of suitable topical formulations are disclosed in U.S. Pat. Nos. 4,139,619 and 4,596,812 which are incorporated herein by reference.
The enantiomers of the invention will be used in an effective amount, that is, in an amount sufficient to promote hair growth or treat hair growth disorders, such that hair growth is increased or produced. A typical topical composition will include from about 0.01 to about 15% by weight, preferably from about 0.1 to about 10% by weight of the composition.
The topical formulations containing the enantiomers of the invention can be applied to the area to be treated such as the scalp in humans, by spraying, dabbing or swabbing to deliver the enantiomer to the region of the hair follicle. The formulations will be applied to the area of treatment on a routine basis prior to, during and subsequent to hair growth, at least once daily, and preferably two or more times daily.
The accompanying Figure is a graph showing the effect of a once daily application of each of the (R)- and (S)- enantiomers described herein on hair growth in male C3H mice.
The following Examples represent preferred embodiments of the present invention.